The broad objective of this project is to characterize the effects of cocaine on the immune system and to investigate whether neuroendocrine mechanisms are involved in cocaine induced immunosuppression. Specifically, this project tests the hypothesis that the activation of the hypothalamic-pituitary-adrenal axis and/or inhibition of central or peripheral monoaminergic uptake system mediates the inhibitory effects of cocaine administration on lymphocyte activities. Specific Aims to be addressed: 1. Aim: To evaluate the acute and subacute effects of cocaine on rapidly responding elements of the immune system. These studies will characterize the inhibitory effects of cocaine on lymphocyte proliferation and cytolytic activities in terms of time and dose dependency. Additional factors which may contribute to the suppression in immune cell activities will also be examined. These will include the effects of cocaine on the distribution of subpopulations of T and B cells, lymphocyte production of IL-2 and monocyte secretion of IL-1. 2. Aim: To assess the subacute effects of cocaine on additional measures of cellular and humoral mediated immunity. These studies will determine the immune consequences of multiple exposures to cocaine on the delayed type hypersensitivity reaction, cytolytic T lymphocyte activity, and T-cell dependent and independent antibody responses. 3. Aim: To investigate whether the effects of cocaine on the immune system are mediated through activation of the hypothalamic-pituitary- adrenal axis. These studies will address whether the suppression of lymphocyte proliferation in cocaine treated animals is mediated by an elevation in plasma ACTH or corticosterone. The effects of cocaine on immune parameters will be examined in adrenalectomized animals and those pretreated with either the glucocorticoid antagonist Ru486 or antisera to rat CRF. 4. Aim: To determine whether the effects of cocaine on lymphocyte activity are the consequence of inhibition of serotonin uptake or another monoamine. These studies will determine whether the administration of serotonergic uptake inhibitors produce similar effects on the immune system as cocaine. If they do, we will then assess whether serotonergic antagonists attenuate the immunosuppressive effects of cocaine through central or peripheral mechanisms. Finally, the effects of other monoamine uptake inhibitors on lymphocyte activity will be determined to evaluate the participation of other amines in the immune effects of cocaine.